Project Summary/Abstract Objective: Major Depressive Disorder (MDD) is one of the largest contributors to the global burden of disease. However little is known about the physiology underlying the emotional symptoms of MDD. Cortisol insensitivity and hyperactivity of the subgenual cingulate (Sgc) are commonly observed physiological changes that occur in MDD, and both resolve with successful treatments. My previous research links these observations to each other and to the neurocircuitry underlying the emotional symptoms of MDD. These data demonstrate that cortisol normally functions to inhibit sadness-induced Sgc activity (s-Sgc). This suggests that cortisol insensitivity could be causing Sgc hyperactivity in MDD, and thus exaggerating the sadness response in patients. The main objectives of this proposal is to 1) understand if cortisol insensitivity in the subgenual cingulate is driving up activity in the region in patients with MDD and 2) identify genetic variants on cortisol receptor genes that may predispose individuals to develop cortisol insensitivity in the s-Sgc circuit. This project will use cortisol administration and functional magnetic resonance imaging to quantify the degree of insensitivity of s-Sgc to cortisol in MDD and healthy controls. The project will also use next-generation sequencing of the 2 cortisol receptor genes to identify genetic risk factors for developing s-Sgc insensitivity to cortisol. Rationale: Understanding the physiology underlying the emotional symptoms of MDD is a critical first step in the development of new evidence-based interventions. This project has the potential to uncover a physiological mechanism that drives the emotional symptoms of depression. It could also identify genetic profiles that are more susceptible, or less susceptible, to developing emotional disturbances associated with MDD. Level & Duration: The proposed research/training is for 1 junior faculty position over 4 years.